Project Summary Neuropeptide somatostatin analogs are important therapeutics for the treatment of hormone secreting tumors with annual sales of ~$2.4B. However, currently available peptide depots are effective in only half the patients with growth hormone secreting tumors, and patients with carcinoid tumors can rapidly become resistant to these drugs. Somatostatin analogs act by stimulating the GPCR sst2A, but the currently available agents cause desensitization via internalization of the same receptor, resulting in reduced or complete loss of efficacy. We hypothesized that biased agonists of sst2A that maintain strong Gi activation, but do not cause desensitization, would normalize hormone levels in a greater percentage of patients and improve efficacy in patients not adequately controlled by currently available agents. In Phase I, we began developing compounds to test this hypothesis using assays for both receptor activation and internalization to identify several small molecule, non-peptide agonists that are indeed potent activators of Gi, but with far less propensity for inducing receptor internalization and desensitization. These early results paved the way for Phase II, in which we optimized the leads identified in Phase I to identify compounds with sub-nanomolar potency, selectivity versus a number of off-target activities, and drug-like properties ultimately leading to a Development Candidate. This compound is effective in both acute and chronic studies of GH and IGF-I suppression in rats, exhibits good drug-like characteristics including oral bioavailability and half-life consistent with anticipated once a day dosing in human, and a good safety margin based on preliminary rat studies. The goal of this Phase IIB project is to optimize process chemistry and prepare material which will then be used to conduct IND enabling toxicology studies. This will enable a Phase I clinical trial of the first orally bioavailable, biased somatostatin agonist for the treatment of hormone secreting tumors. Our innovative approach towards the identification of such an agent has proactively incorporated a set of receptor regulatory assays, and if successful, promises to deliver a new cost effective therapeutic agent with a novel pharmacological profile that leads to both improved efficacy and durability of effect. Importantly, the GPCR family is a rich source of proven targets for drug discovery, which share common regulatory and signaling mechanisms. Therefore, if successful, this work will not only provide improved agents for patients with hormone secreting tumors, but will also support a general novel strategy for optimizing agonist drugs that can be exploited to target many other GPCRs.